New and unprecedented changes in customer demands, globalization, cost pressures, innovative product development strategies to shorten product development time, and changing external landscape with reduction of trade barriers, poses challenges and opportunities for the manufacturing industry. Customer demands and needs require modification and reconfiguration of existing manufacturing and assembly plants as well as creation and setup of new ‘Greenfield’ facilities in developing countries. Currently, the solutions provided by most service providers focuses on limited elements of the solution methodology. We have developed an integrated methodology to perform virtual plant commissioning using digital manufacturing, design for six sigma and lean manufacturing principles. Starting from product definition, the paper goes into the depth of macro and micro level plant layout, line layout and definition, line simulation, line balancing, optimization of line and process plans, tooling station detail, material flow, and kitting of modules. It integrates design at plant level, line level, station level and equipment level and as a result of this approach; multiple what-if scenarios are evaluated and visualized in 3D, early on in the product development process, before the need for investment in plant infrastructure. In addition, this methodology helps simulate the movement of a 3D digital prototype through a virtual plant; thereby helping reduce ‘unpredicted’ product launch costs and corrective tear-up of physical infrastructure.